A large number of imaging studies performed during the course of radiation treatment have indicated substantial patient setup and soft tissue position variation. Consequently, significant temporal variation of dose distribution in organs of interest (TVODD) exists during the course of radiotherapy and presents itself as one of the most difficult problems for quantitative radiotherapy analysis. Without fully understanding this variation, the treatment outcome, particularly normal tissue dose response, cannot be correctly correlated to the prescribed dose, thereby preventing reliable treatment evaluation and optimization. This fundamental problem is further exacerbated for a high conformal treatment. It is our hypothesis that quantifying TVODD in radiotherapy is essential for realizing the potential of advanced treatment technologies (e.g. IMRT). Knowledge of the temporal variation of the dose distribution in critical normal structures can be exploited to improve ongoing treatment, if the variation is quantified. Otherwise, TVODD remains as a major source of uncertainty in the treatment process. To test our hypothesis, the following Specific Aims will be pursued: (1) Integrate a soft tissue biomechanics model and finite element algorithm into the image based organ registration and evaluation system, and perform a study to determine the sensitivity of the registration model to variations of tissue mechanical properties and organ boundary conditions, (2) Validate the image based organ registration, in vivo, by using multiple CT images collected from patients with embedded radiomarkers, (3) Perform clinical studies to determine the potential impact of temporal variation of organ dose distribution on treatment planning evaluation and decisions. Explore practical methods to include temporal variation of organ dose distribution, estimated from image feedback, in treatment planning optimization.